We propose experiments in years 21 to 25 of a successful Program to investigate the molecular basis of cell transformation by DNA tumor viruses. The five participating laboratories are organized into two clusters. The papillomavirus cluster will focus on the Human papillomaviruses, which have been strongly implicated in the genesis of common human cancers, particularly cervical cancer. Dr. Brandsma will continue her attempts to optimize papilloma induction with cloned HPV16DNA, a project with the potential to represent a real breakthrough in papillomavirus research. Dr. DiMaio will continue his mechanistic studies on the HPV16 E5 transforming protein. The Herpes virus cluster will focus on Epstein-Barr virus and related viruses associated with lymphoproliferative diseases and other cancers. In related projects, Drs. Miller and Maizels will explore the functions of cellular DNA binding proteins implicated in regulating the viral life cycle and structure of the viral DNA. Dr. Steitz will continue her analysis of the role of small viral-encoded RNAs in transformation and other aspects of host cell metabolism. In addition, a protein expression and purification core will provide essential services to the Program. This Program represents the significant commitment of the Yale University School of Medicine and the participating investigators to studies that may well have direct relevance to understanding the cause of human cancer.